The Role of 64/128-Slice Multidetector Computed Tomography to Assess the Progression of Coronary Atherosclerosis Sherif W. Ayad, Eman M. ElSharkawy, Salah M. ElTahan, Mohamed A. Sobhy and Reem H. Laymouna Department of Cardiology, Alexandria University, Alexandria, Egypt.
ABSTRACT Objectives: We studied the progression of coronary atherosclerosis over time as detected by multidetector computed tomography (MDCT) in relation to risk factors and plaque composition. Background: Studies using MDCT are limited to the assessment of the degree of stenosis without taking into consideration the plaque composition that is seen by MDCT. Methods: This study included 200 patients, complaining of chest pain and referred to do 64/128-contrast–enhanced MDCT for the second time, and both studies were retrieved and evaluated for the presence of plaque, plaque type, vessel wall remodeling, percent area, and diameter stenosis and compared in both studies. Plaque progression over time and its association with risk factors were determined. Results: We included 200 patients, and 348 plaques were detected by 64/128 MDCT. The duration between follow-up and baseline studies was 25.9 ± 19.2 month. In all, 200 plaques showed progression (57.47%), 122 were stable (35.06%), and 26 regressed (7.47%). In longitudinal regression analysis, the presence of history of diabetes mellitus and dyslipidemia and the absence of intraplaque calcium deposits were independently associated with plaque pro gression over time (P , 0.0001). CONCLUSION: Coronary plaque burden of patients with chest pain and no history of acute coronary syndrome significantly increased over time. Progression is dependent on plaque composition and cardiovascular risk factors. Larger studies and longer follow-up period are needed to confirm the determinant factors for plaque progression. KEYWords: cardiac MDCT, plaque progression, atherosclerosis Citation: Ayad et al. The Role of 64/128-Slice Multidetector Computed Tomography to Assess the Progression of Coronary Atherosclerosis. Clinical Medicine Insights: Cardiology 2015:9 47–52 doi: 10.4137/CMC.S20606.
Copyright: © the authors, publisher and licensee Libertas Academica Limited. This is an open-access article distributed under the terms of the Creative Commons CC-BY-NC 3.0 License.
Received: September 30, 2014. ReSubmitted: March 15, 2015. Accepted for publication: March 18, 2015.
aper subject to independent expert blind peer review by minimum of two reviewers. All P editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti-plagiarism scanning. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties. This journal is a member of the Committee on Publication Ethics (COPE).
Academic editor: Thomas E. Vanhecke, Editor in Chief TYPE: Original Research Funding: Authors disclose no funding sources. Competing Interests: Authors disclose no potential conflicts of interest. Correspondence: [email protected]
Introduction
According to the World Health Organization, cardiovascu lar disease is the number one cause of death. Globally more people die annually from cardiovascular disorders than from any other cause.1 In particular, the Global Burden of Dis ease study classified ischemic heart disease as the leading cause of global mortality, accounting for 1.4 million deaths in the developed world and 5.7 million deaths in developing regions. 2 Assessment of the coronary plaque burden and disease progression added to the understanding of the natural his tory and pathophysiology of coronary artery disease (CAD) and is a surrogate end point for the evaluation of novel therapeutics.3,4 Invasive modalities such as intravascular ultrasound (IVUS) and serial selective quantitative coronary angiogra phy (QCA) are considered gold standard methods to mea sure the progression of atherosclerotic plaque and stenosis over time.5 However, these modalities are limited by their
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invasive nature and by the specific characteristics they are able to measure.6 Multidetector computed tomography coronary angio graphy (MDCT) is a non invasive modality the can detect plaque composition and vessels wall changes as remodeling and provides actual plaque burden assessment. Although a few serial studies with MDCT have been published,7,8 most prior analyses were confined to a small seg ment of the coronary tree or a specific subset of lesions (ie, noncalcified). In the present study, our objective was to study the natural history of coronary atherosclerosis using 64/128 MDCT and to assess the serial changes in coronary plaque size, lumen dimensions, and arterial remodeling over an interval of time.
Methods
Patients. The study was conducted on 200 consecutive patients who underwent repeated coronary MDCT. This Clinical Medicine Insights: Cardiology 2015:9
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study complied with the principles of Helsinki. The first MDCT study could be retrieved retrospectively and reevalu ated. Patients with a history of revascularization, intervention between the two studies, atrial fibrillation, or creatinine clear ance ,50 mL/min were excluded. All patients gave written informed consent, and the study protocol was approved by the institutional ethical committee. History concerning the risk factors (diabetes mellitus [DM], hypertension, smoking, dyslipidemia, family history [FH]) and history of ACS (acute coronary syndrome) were noted. Coronary MDCT acquisition. Baseline and follow-up cardiac CT scans were performed using 64/128-slice MDCT (Toshiba Aquilion system) with the following parameters: gantry rotation time of 400 ms, slice thickness of 0.5 mm, heli cal retrospective gating and reconstruction interval of 1 mm. Patients were fasting for 4–6 hours. Oral beta-blockers were given to all patients with a heart rate more than 60 bpm, unless contraindicated. An intravenous (IV) nonionic contrast (lop amidol 370) (0.5–2.0 mL/kg, 80 mL maximum volume) was injected followed by a 10- to 30-mL saline flush at rates rang ing from 1.5 to 2.5 mL/s. Image acquisition was performed with a 64-slice MDCT (Aquilion 64 Toshiba). First, a non– contrast-enhanced, prospectively electrocardiogram-triggered calcium score was performed at 75% of the R–R interval. The automatic bolus triggering technique was used for initiating image acquisition. An automatic raw data motion analysis tool was used to determine the optimal systolic and diastolic phases for reconstruction. Additional reconstructions at end systole (30% to 40% of the R–R interval) and mid-diastole (70% to 80% of the R–R interval) were routinely reconstructed. All phases were evaluated to identify the optimal phase for evalu ation of each coronary artery. Coronary MDCT image analysis. All data sets were trans ferred to an offline Vitrea 3D workstation for analysis using a semiautomated plaque analysis software.Two experienced observ ers blinded to the sequence of imaging evaluated the scans. All three vessels were assessed in every patient, and all anatomically available segments were examined. The segments of poor quality due to stack, movement artifacts, or extreme calcification were excluded from analysis. The following parameters were calculated per segment and per patient: • a.
QCA-like parameters Minimum lumen diameter (MLD) is the narrowest lumen diameter within each segment. b. Percent diameter stenosis (%DS) = [(reference diameter − MLD)/reference diameter] × 100. • a.
IVUS-like parameters: Percent atheroma volume = [(total vessel volume − total lumen volume)/total vessel volume)] × 100. b. Total atheroma volume (TAV) = total vessel volume − TAV. 48
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Percentage change in TAV = [(TAV follow-up − TAV baseline)/TAV baseline)] × 100. d. Minimum lumen area (MLA). e. Percent area stenosis (%AS) = [(reference lumen area − MLA)/reference lumen area] × 100. c.
•
Coronary remodeling A change in vessel area from baseline to follow-up was calculated. Increase in vessel area was considered posi tive remodeling and decrease was considered negative remodeling.9 Statistical analysis was done using IBM SPSS software package version 20, using chi-square test, F-test (analysis of variance), and Kruskal–Wallis test. Significant test results were quoted as two-tailed probabilities.
Results
Among the 200 patients, 170 patients (85%) were males and 30 patients (15%) were females with a mean age of 60.5 ± 7.8 years. As for risk factors, 95 patients (47.5%) had DM, 155 patients (77.5%) had hypertension, 110 patients (55%) were current smokers, 130 patients (65%) were having a history of dyslipidemia, and 80 patients (40%) had a FH of CAD. The mean duration between the baseline MDCT and the first follow-up was 25.9 ± 19.2 months ranging from 2 to 72 months. A total of 348 plaques were detected, 200 atherosclerotic plaques (47.5%) had an increase in DS (change in %DS .10), 122 plaques (35.05%) had no change in %DS, and 26 plaques had a decrease in %DS. A total of 205 plaques (58.9%) had an increase in AS (change in %AS .10), 118 plaques (33.9%) had no change in %AS, and 20 plaques (5.7%) had a decrease in %AS. Two hundred and thirty plaques (66.1%) had increased in TAV (% change in TAV .20), 40 plaques (11.5%) had no change in volume, and 78 plaques (22.4%) had decreased in volume. To ensure the accuracy of change in plaque characters, we considered the change of the atherosclerotic plaque is significant if two of the three above characters (%DS, %AS, and% change in TAV ) had increased, regressed, or did not change. From the above criteria, we classified plaques as follows: 200 plaques (57.47%) had progressed, 122 plaques (35.06%) had no change, and 26 plaques (7.47%) regressed. In our results, the most statistically significant risk fac tors associated with plaque progression were DM and pre sence of dyslipidemia. As seen in Table 1, from the total of 200 progressed plaques, 64.1% (128/200) were diabetics, while none of the regressed plaques were found in patients with DM (P . 0.001). Also we found that 65% (130/200) of progressed plaques were found in patients with dyslipidemia comparable to 20% (5/26) of regressed plaques (P = 0.012). The other risk
MDCT to assess the progression of coronary atherosclerosis Table 1. Comparison between the studied groups according to risk factors. Progressed (n = 200)
Regressed (n = 26)
No change (n = 122)
No
%
No
%
No
%
DM
128
64.1
0
0.0
25
Dyslipidemia
130
65
5
20.0
Hypertension
159
79.5
16
Smoking
108
53.8
5
FH
92
46.2
5
p
χ2
MC
20.8
15.543*
,0.001*
71
58.3
8.636*
0.012*
60
107
87.5
2.139
0.288
20
66
54.2
0.363
0.866
20
56
45.8
1.274
0.593
Notes: Values were presented as numbers with percentages. χ : value of chi-square for comparing between the three studied groups. *Statistically significant at P # 0.05. Abbreviation: MC, Monte Carlo test. 2
Cases. Figures 3, 4 and 5 provide examples of progres sion and regression of coronary plaques detected by MDCT.
factors did not reach statistically significant difference between the groups. Of the 200 plaques that have progressed, 149 plaques (74.5%) were soft plaques, 36 plaques (18%) were calcific, and 15 plaques (7.5%) were mixed calcific plaques as seen in Table 2. Of the 122 stable plaques, 61 plaques (50%) were calcific plaques, 41 plaques (33.7%) were soft plaques, and 20 plaques (16.3%) were mixed calcific plaques. This proved the association between plaque stabilization and the presence of intraplaque calcium deposit and progres sion of the plaque in the absence of calcium (P = 0.001). Of the 200 plaques that progressed, 16 plaques (8%) had no remodeling, 144 plaques (72%) had positive remodel ing, and 40 plaques (20%) had negative remodeling. Of the 122 stable plaques, only 5 plaques (4.2%) had no remodeling, 66 plaques (54.1%) had negative remodeling, and 51 plaques (41.7%) had positive remodeling. Of the 26 plaques that regressed, 11 plaques (42.3%) had negative remodeling and 15 plaques (57.7%) had positive remodeling. So, there was no significant association between vascular remodeling and plaque progression (P = 0.228) (as seen in Table 3). Changes of atherosclerotic plaque over time and its association with cardiovascular risk factors. In univariate longitudinal regression models, DM and the presence of dys lipidemia and absence of calcification were significantly asso ciated with progression of any atherosclerotic plaque (Table 4 and Fig. 1). The duration of follow-up did not affect the progression or regression of the plaques significantly (Fig. 2).
Discussion
Progressive atherosclerotic disease and its clinical sequel remain the number one cause of mortality in the United States. The majority of patients with ACS present with unstable angina, acute myocardial infarction, or sudden cardiac death secondary to sudden luminal thrombosis.10 Until recently, the prevailing clinical perception of ath erosclerosis was that of advancing luminal stenosis with less attention paid to the condition of the vessel wall. In order to follow-up patients with CAD and assess the pro gression of atheromatous plaques, we need to use a noninvasive, feasibly repeatable method with low interobserver variability. MDCT enables an accurate noninvasive identification and quantification of coronary plaques. The extent of coro nary calcium is a surrogate marker for total plaque burden. However, there is a striking heterogeneity among human atherosclerotic lesions, and coronary plaques often consist of noncalcified tissue.10,11 Thus, even in coronary vessels with out calcified plaques, severe atherosclerosis may be present. Hence, a more precise assessment of coronary atheroscle rotic plaque burden and disease progression by noninva sive imaging tools that can detect and characterize calcified and noncalcified plaques can be expected to add important information, but it remains a challenge even by invasive methods.
Table 2. Comparison between the three studied groups according to plaque calcification. Progressed (n = 200)
Regressed (n = 26)
No change (n = 122)
No
%
No
%
No
%
Soft
149
74.5
0
0.0
41
33.7
Calcific
36
18
21
80.7
61
50.0
Mixed
15
7.5
5
19.3
20
16.3
p
χ2
MC
16.775*
,0.001*
Notes: χ2: value of chi-square for comparing between the three studied groups. *Statistically significant at P # 0.05. Abbreviation: MC, Monte Carlo test.
Clinical Medicine Insights: Cardiology 2015:9
49
Ayad et al Table 3. Comparison between the three studied groups according to vascular remodeling. Progressed (n = 200)
Regressed (n = 26)
No change (n = 122)
No
%
No
%
No
%
Absent
16
8
0
0.0
5
4.2
Negative
144
72
11
42.3
66
54.1
Positive
40
20
15
57.7
51
41.7
p
χ2
MC
5.457
0.228
VR
Notes: χ2: value of chi-square for comparing between the three studied groups. Abbreviations: MC, Monte Carlo test; VR, vascular remodeling.
Table 4. Binary logistic regression for factors affecting plaque progression.
Sex Age
B
S.E
Sig.
OR
95% CI
DM
LL
UL
HTN
Sex
0.231
1.288
0.858
1.260
0.101
15.729
Smoking
Age
−0.101
0.057
0.073
0.904
0.809
1.010
Dyslipid
DM
3.146
1.052
0.003*
23.246
2.956
182.785
HTN
−1.244
1.367
0.363
0.288
0.020
4.201
Smoking
−1.500
0.932
0.107
0.223
0.036
1.386
Dyslipid
2.095
1.202
0.081
8.128
0.771
85.719
FH
−1.436
1.065
0.177
0.238
0.029
1.918
ACS
−1.027
1.077
0.340
0.358
0.043
2.954
Duration
0.007
0.028
0.811
1.007
0.953
1.063
Y
−2.818
1.138
0.013*
0.060
0.006
0.556
M
−1.395
1.162
0.230
0.248
0.025
2.419
Notes: Qualitative data were described using number and percent and were compared using chi-square or Monte Carlo test. Normally quantitative data were expressed as mean ± standard deviation and compared using Student’s t-test. While abnormally distributed data were expressed using Median (Min. – Max.) and were compared using Mann–Whitney test. *Statistically significant at P # 0.05. Abbrevations: HTN, hypertension; Dyslipid, dyslipidemia; Ca, calcium.
We aimed to study the role of 64/128-MDCT using both QCA and IVUS-like parameters to assess plaque vol ume, composition, and degree of stenosis and see the changes of these parameters over time. In this study, we did follow-up of 200 patients with chest pain but without ACS for 25.9 ± 19.2 months, using a semi quantitative assessment of coronary plaque burden. We found a significantly increased TAV, %AS, and %DS in 57.47% of plaques; regression in 7.4%; and stabilization in 35.06%. Our results further indicate that there are differences in progression rate according to plaque composition as we found no significant progression for calcified plaque while noncal cified plaque progressed significantly over time (χ2 = 16.775, P , 0.0001). Progression of plaque was significantly associated with the presence of cardiovascular risk factors in adjusted analysis as DM and dyslipidemia. 50
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ACS Duration Ca-1 Y Ca-1 M 0.001
0.01
0.1
1 OR
10
100
1000
Figure 1. Predictors of plaque progression.
80 70 60
Duration (months)
Ca-1
FH
50 40 30 20 10 0 Decrease or no change
Increase
Plaque progression
Figure 2. Relation of follow-up duration and atherosclerotic plaque changes.
Previous papers have shown that MDCT is comparable to QCA angiography regarding lumen stenosis assessment9,12; but QCA is a lumenography lacking the detection of the vessel wall changes, remodeling, and plaque characterization. Similarly, IVUS and MDCT comparative studies8,10 have shown that the MDCT can reasonably evaluate atherosclerotic plaque size, remodeling, eccentricity, and composition, despite
MDCT to assess the progression of coronary atherosclerosis
Figure 3. Patient No. 9, plaque No. 19: MDCT showing regression of proximal LAD soft nonobstructive plaque: (A) baseline study and (B) follow-up study.
Figure 4. Patient No. 21, plaque No. 127: MDCT showing stable LAD mixed obstructive plaque: (A) baseline study and (B) follow-up study.
Figure 5. Patient No. 21, plaque No. 128, 129: MDCT showing progression of proximal and distal RCA soft obstructive plaques: (A) baseline study and (B) follow-up study.
the acknowledged limitations of the technique. Voros et al.13 suggested that quantitative MDCT angiography could be accept ably used in population-based approaches, given the small mean differences between MDCT and IVUS measurements. Most prior IVUS studies comparable with MDCT dem onstrated lesions in the proximal segments of the three main vessels with high accuracy, but they were not able to study the distal and branching vessels by both techniques and compar ing the plaque site and composition due to the invasive nature and long procedure of IVUS study. Butler et al.14 revealed that the extent and nature of over all CAD, defined as the cumulative stenotic and nonstenotic, calcified and noncalcified atherosclerosis burden, are underes timated by invasive coronary angiography and more accurately quantified with IVUS. MDCT is inferior to IVUS but may constitute an attractive noninvasive alternative to assess over all CAD burden.15
Plaque characterization. In our study, there was an association between plaque stabilization with the presence of calcium deposits in the plaque and plaque progression with the absence of calcium (P = 0.001). Of the 200 progressed plaques, 74.5% were soft noncalcific plaques and 50% of the stable plaques were calcific plaques. In the analysis by Lehman et al.16, 69 patients were included who presented with acute chest pain to the emergency department but initially showed no evidence of acute coro nary syndromes. All patients underwent contrast-enhanced 64-slice CT at baseline and after 2 years. There was significant progression in the mean number of cross-sections containing any plaque (16.5 ± 25.3 vs. 18.6 ± 25.5, P = 0.01) and noncalci fied plaque (3.1 ± 5.8 vs. 4.4 ± 7.0, P = 0.04) but not calcified plaque (13.3 ± 23.1 vs. 14.2 ± 22.0, P = 0.2). So, soft plaques were more liable for progression and vul nerability, and calcified plaques tend to be more stable. The study by Schmid et al.17 was conducted to measure the change in noncalcified coronary plaque volume in the left main coronary artery and in the proximal left anterior descend ing coronary artery over time using 64-slice MDCT. Fifty patients in whom noncalcified lesions had been detected on baseline MDCT received follow-up scans after an interval of 17 ± 6 months. They found that there is a significant increase of the amount of noncalcified plaque, which was observed over a mean interval of 17 months. In our study, the most statistically significant (P = 0.001) risk factor associated with plaque progression is DM and dyslipidemia. Wong et al.18 revealed that individuals with metabolic syndrome (MetS) and DM have a greater incidence and abso lute progression of coronary artery calcium (CAC) compared with individuals without these conditions, with progression also predicting coronary heart disease events in those with MetS and DM.19 This study sought to examine and compare the incidence and progression of CAC among persons with MetS and DM versus those with neither condition. The MESA (Multiethnic Study of Atherosclerosis) included 6,814 African American, Asian, Caucasian, and Hispanic adults, free of cardiovascular disease at baseline. Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals [CI]) for incident CAC were 1.7 (95% CI: 1.4–2.0), 1.9 (95% CI: 1.4–2.4), and 1.8 (95% CI: 1.4–2.2) (all P , 0.01), and absolute differences in mean progression (volume score) were 7.8 (95% CI: 4.0–11.6; P , 0.01), 11.6 (95% CI: 2.7–20.5; P , 0.05), and 22.6 (95% CI: 17.2–27.9; P , 0.01) for those with MetS with out DM, DM without MetS, and both DM and MetS, respec tively. Similar findings were seen in an analysis using Agatston calcium score. In addition, progression predicted coronary heart disease events in those with MetS without DM (adjusted hazard ratio: 4.1, 95% CI: 2.0–8.5, P , 0.01) and DM (adjusted hazard ratio: 4.9 [95% CI: 1.3–18.4], P , 0.05) among those in the highest tertile of CAC increase versus no increase. Clinical Medicine Insights: Cardiology 2015:9
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So in both studies, DM is definitely, especially if uncon trolled, associated with atherosclerotic plaque progression. In our study, dyslipidemia is the second statistically sig nificant (P = 0.012) risk factor. Of a total of 200 plaques that progressed, 130 patients (65%) were dyslipidemic patients. Hoffmann et al.19 found that the effect of statin treat ment on noncalcified plaques was significant after adjusting for LDL levels and cardiac risk factors.20,21 This study supports ours, as with dyslipidemia and uncon trolled blood levels, LDL is strongly associated with plaque progression, and controlling of blood levels of LDL with sta tins is associated with atherosclerotic plaque stabilization.
Study Limitations
The relatively small number of patients studied was the main limitation in this study. Selection bias was another limitation, as the inclusion of the patients was based on the clinicians’ opinion without clear preset recommendations. Repeating this study at a wider scale might yield different results. In addition, this being a retrospective study made us unable to take detailed history about the medications, blood pressure, and dyslipidemic and diabetic control.
Conclusion
Coronary plaque burden of patients with acute chest pain sig nificantly increases over time and the progression is dependent on plaque composition, especially for soft noncalcified plaque when compared to calcified plaque. Progression is further associated with cardiovascular risk profile at baseline. Larger studies are needed to confirm these results and to determine whether the MDCT can be used for noninvasive monitor ing and follow-up of coronary atherosclerosis in high-risk patients.
Acknowledgment
This research was originally conducted and presented for the Master of Cardiology thesis of Reem H. Laymouna, under the supervision of Mohamed A. Sobhy, Salah M. ElTahan and Sherif W. Ayad, at Alexandria University.
Author Contributions
Designed the study: SME, MAS. Analyzed the data: EMS. Wrote the first draft: SWA. Contributed to writing: RL. Arranged the paper: EMS. Made critical revisions: EMS. All authors reviewed and approved of the final manuscript. References
1. Santulli G. Epidemiology of cardiovascular disease in the 21st century: updated numbers and updated facts. J Cardiovasc Dis. 2013;1(1):1–2. 2. Pagidipati NJ, Gaziano TA. Estimating deaths from cardiovascular diseases: a review from global methodologies of mortality measurement. Circulation. 2013;127(6):749–56.
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3. De Feyter PJ, Serruys PW, Davies MJ, Richardson P, Lubsen J, Oliver MF. Quantitative coronary angiography to measure progression and regression of coronary atherosclerosis. Value, limitations, and implications for clinical trials. Circulation. 1991;84(1):412–23. 4. Mintz GS, Garcia-Garcia HM, Nicholls SJ, et al. Clinical expert consensus document on standards for acquisition, measurement and reporting of intravas cular ultrasound regression/progression studies. EuroIntervention. 2011;6(9): 1123–30. 5. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med. 2008;359(22):2324–36. 6. Weustink AC, Mollet NR, Neefjes LA, et al. Diagnostic accuracy and clini cal utility of noninvasive testing for coronary artery disease. Ann Intern Med. 2010;152(10):630–9. 7. Hoffmann U, Moselewski F, Nieman K, et al. Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syn drome and stable lesions in stable angina by multidetector computed tomogra phy. J Am Coll Cardiol. 2006;47(8):1655–62. 8. Papadopoulou SL, Neefjes LA, Schaap M, et al. Detection and quantification of coronary atherosclerotic plaque by 64-slice multidetector CT: a system atic head-to-head comparison with intravascular ultrasound. Atherosclerosis. 2011;219(1):163–70. 9. Leber AW, Becker A, Knez A, et al. Accuracy of 64-slice computed tomogra phy to classify and quantify plaque volumes in the proximal coronary system. A comparative study using intravascular ultrasound. J Am Coll Cardiol. 2006;47:672–7. 10. Burgstahler C, Reimann A, Beck T, et al. Influence of a lipid-lowering therapy on calcified and noncalcified coronary plaques monitored by multislice detec tor computed tomography: results of the new age II Pilot Study. Invest Radiol. 2007;42(3):189–95. 11. Inoue K, Motoyama S, Sarai M, et al. Serial coronary ct angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention. JACC Cardiovasc Imaging. 2010;3(7):691–8. 12. Nicholls SJ, Sipahi I, Tuzcu EM. Assessment of progression and regression of coronary atherosclerosis by intravascular ultrasound. A new paradigm shift? Rev Esp Cardiol. 2006;59(1):57–66. 13. Voros S, Rinehart S, Qian Z, et al. Prospective validation of standardized, 3dimensional, quantitative coronary computed tomographic plaque measurements using radiofrequency backscatter intravascular ultrasound as reference standard in intermediate coronary arterial lesions: results from the ATLANTA (Assess ment of tissue characteristics, lesion morphology, and hemodynamics by angiog raphy with fractional flow reserve, intravascular ultrasound and virtual histology, and noninvasive computed tomography in atherosclerotic plaques) I study. JACC Cardiovasc Interv. 2011;4(2):198–208. 14. Butler J, Shapiro M, Reiber J, et al. Extent and distribution of coronary artery disease: a comparative study of invasive versus noninvasive angiography with computed angiography. Am Heart J. 2007;153(3):378–84. 15. How BJ, Abraham A, Wells GA, et al. Diagnostic accuracy and impact of com puted tomographic coronary angiography on utilization of invasive coronary angiography. Circ Cardiovasc Imaging. 2009;2(1):16–23. 16. Lehman SJ, Schlett CL, Bamberg F, et al. Assessment of coronary plaque pro gression in coronary computed tomography angiography using a semiquantita tive score. JACC Cardiovasc Imaging. 2009;2(11):1262–70. 17. Schmid M, Achenbach S, Ropers D, et al. Assessment of changes in noncalcified atherosclerotic plaque volume in the left main and left anterior descend ing coronary arteries over time by 64-slice computed tomography. Am J Cardiol. 2008;101(5):579–84. 18. Wong ND, Nelson JC, Granston T, et al. Metabolic syndrome, diabetes, and incidence and progression of coronary calcium: the multiethnic study of athero sclerosis study. JACC Cardiovasc Imaging. 2012;5(4):358–66. 19. Hoffmann H, Frieler K, Schlattmann P, Hamm B, Dewey M. Influence of statin treatment on coronary atherosclerosis visualised using multidetector computed tomography. Eur Radiol. 2010;20(12):2824–33. 20. Uehara M, Funabashi N, Mikami Y, Shiina Y, Nakamura K, Komuro I. Quan titative effect of atorvastatin on size and content of non-calcified plaques of coronary arteries 1 year after atorvastatin treatment by multislice computed tomography. Int J Cardiol. 2008;130(2):269–75. 21. Oberoi S, Schoepf UJ, Meyer M, et al. Progression of arterial stiffness and coronary atherosclerosis: longitudinal evaluation by cardiac CT. Am J Roentgenol. 2013;200(4):798–804.
ABSTRACT Objectives: We studied the progression of coronary atherosclerosis over time as detected by multidetector computed tomography (MDCT) in relation to risk factors and plaque composition. Background: Studies using MDCT are limited to the assessment of the degree of stenosis without taking into consideration the plaque composition that is seen by MDCT. Methods: This study included 200 patients, complaining of chest pain and referred to do 64/128-contrast–enhanced MDCT for the second time, and both studies were retrieved and evaluated for the presence of plaque, plaque type, vessel wall remodeling, percent area, and diameter stenosis and compared in both studies. Plaque progression over time and its association with risk factors were determined. Results: We included 200 patients, and 348 plaques were detected by 64/128 MDCT. The duration between follow-up and baseline studies was 25.9 ± 19.2 month. In all, 200 plaques showed progression (57.47%), 122 were stable (35.06%), and 26 regressed (7.47%). In longitudinal regression analysis, the presence of history of diabetes mellitus and dyslipidemia and the absence of intraplaque calcium deposits were independently associated with plaque pro gression over time (P , 0.0001). CONCLUSION: Coronary plaque burden of patients with chest pain and no history of acute coronary syndrome significantly increased over time. Progression is dependent on plaque composition and cardiovascular risk factors. Larger studies and longer follow-up period are needed to confirm the determinant factors for plaque progression. KEYWords: cardiac MDCT, plaque progression, atherosclerosis Citation: Ayad et al. The Role of 64/128-Slice Multidetector Computed Tomography to Assess the Progression of Coronary Atherosclerosis. Clinical Medicine Insights: Cardiology 2015:9 47–52 doi: 10.4137/CMC.S20606.
Copyright: © the authors, publisher and licensee Libertas Academica Limited. This is an open-access article distributed under the terms of the Creative Commons CC-BY-NC 3.0 License.
Received: September 30, 2014. ReSubmitted: March 15, 2015. Accepted for publication: March 18, 2015.
aper subject to independent expert blind peer review by minimum of two reviewers. All P editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti-plagiarism scanning. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties. This journal is a member of the Committee on Publication Ethics (COPE).
Academic editor: Thomas E. Vanhecke, Editor in Chief TYPE: Original Research Funding: Authors disclose no funding sources. Competing Interests: Authors disclose no potential conflicts of interest. Correspondence: [email protected]
Introduction
According to the World Health Organization, cardiovascu lar disease is the number one cause of death. Globally more people die annually from cardiovascular disorders than from any other cause.1 In particular, the Global Burden of Dis ease study classified ischemic heart disease as the leading cause of global mortality, accounting for 1.4 million deaths in the developed world and 5.7 million deaths in developing regions. 2 Assessment of the coronary plaque burden and disease progression added to the understanding of the natural his tory and pathophysiology of coronary artery disease (CAD) and is a surrogate end point for the evaluation of novel therapeutics.3,4 Invasive modalities such as intravascular ultrasound (IVUS) and serial selective quantitative coronary angiogra phy (QCA) are considered gold standard methods to mea sure the progression of atherosclerotic plaque and stenosis over time.5 However, these modalities are limited by their
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invasive nature and by the specific characteristics they are able to measure.6 Multidetector computed tomography coronary angio graphy (MDCT) is a non invasive modality the can detect plaque composition and vessels wall changes as remodeling and provides actual plaque burden assessment. Although a few serial studies with MDCT have been published,7,8 most prior analyses were confined to a small seg ment of the coronary tree or a specific subset of lesions (ie, noncalcified). In the present study, our objective was to study the natural history of coronary atherosclerosis using 64/128 MDCT and to assess the serial changes in coronary plaque size, lumen dimensions, and arterial remodeling over an interval of time.
Methods
Patients. The study was conducted on 200 consecutive patients who underwent repeated coronary MDCT. This Clinical Medicine Insights: Cardiology 2015:9
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study complied with the principles of Helsinki. The first MDCT study could be retrieved retrospectively and reevalu ated. Patients with a history of revascularization, intervention between the two studies, atrial fibrillation, or creatinine clear ance ,50 mL/min were excluded. All patients gave written informed consent, and the study protocol was approved by the institutional ethical committee. History concerning the risk factors (diabetes mellitus [DM], hypertension, smoking, dyslipidemia, family history [FH]) and history of ACS (acute coronary syndrome) were noted. Coronary MDCT acquisition. Baseline and follow-up cardiac CT scans were performed using 64/128-slice MDCT (Toshiba Aquilion system) with the following parameters: gantry rotation time of 400 ms, slice thickness of 0.5 mm, heli cal retrospective gating and reconstruction interval of 1 mm. Patients were fasting for 4–6 hours. Oral beta-blockers were given to all patients with a heart rate more than 60 bpm, unless contraindicated. An intravenous (IV) nonionic contrast (lop amidol 370) (0.5–2.0 mL/kg, 80 mL maximum volume) was injected followed by a 10- to 30-mL saline flush at rates rang ing from 1.5 to 2.5 mL/s. Image acquisition was performed with a 64-slice MDCT (Aquilion 64 Toshiba). First, a non– contrast-enhanced, prospectively electrocardiogram-triggered calcium score was performed at 75% of the R–R interval. The automatic bolus triggering technique was used for initiating image acquisition. An automatic raw data motion analysis tool was used to determine the optimal systolic and diastolic phases for reconstruction. Additional reconstructions at end systole (30% to 40% of the R–R interval) and mid-diastole (70% to 80% of the R–R interval) were routinely reconstructed. All phases were evaluated to identify the optimal phase for evalu ation of each coronary artery. Coronary MDCT image analysis. All data sets were trans ferred to an offline Vitrea 3D workstation for analysis using a semiautomated plaque analysis software.Two experienced observ ers blinded to the sequence of imaging evaluated the scans. All three vessels were assessed in every patient, and all anatomically available segments were examined. The segments of poor quality due to stack, movement artifacts, or extreme calcification were excluded from analysis. The following parameters were calculated per segment and per patient: • a.
QCA-like parameters Minimum lumen diameter (MLD) is the narrowest lumen diameter within each segment. b. Percent diameter stenosis (%DS) = [(reference diameter − MLD)/reference diameter] × 100. • a.
IVUS-like parameters: Percent atheroma volume = [(total vessel volume − total lumen volume)/total vessel volume)] × 100. b. Total atheroma volume (TAV) = total vessel volume − TAV. 48
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Percentage change in TAV = [(TAV follow-up − TAV baseline)/TAV baseline)] × 100. d. Minimum lumen area (MLA). e. Percent area stenosis (%AS) = [(reference lumen area − MLA)/reference lumen area] × 100. c.
•
Coronary remodeling A change in vessel area from baseline to follow-up was calculated. Increase in vessel area was considered posi tive remodeling and decrease was considered negative remodeling.9 Statistical analysis was done using IBM SPSS software package version 20, using chi-square test, F-test (analysis of variance), and Kruskal–Wallis test. Significant test results were quoted as two-tailed probabilities.
Results
Among the 200 patients, 170 patients (85%) were males and 30 patients (15%) were females with a mean age of 60.5 ± 7.8 years. As for risk factors, 95 patients (47.5%) had DM, 155 patients (77.5%) had hypertension, 110 patients (55%) were current smokers, 130 patients (65%) were having a history of dyslipidemia, and 80 patients (40%) had a FH of CAD. The mean duration between the baseline MDCT and the first follow-up was 25.9 ± 19.2 months ranging from 2 to 72 months. A total of 348 plaques were detected, 200 atherosclerotic plaques (47.5%) had an increase in DS (change in %DS .10), 122 plaques (35.05%) had no change in %DS, and 26 plaques had a decrease in %DS. A total of 205 plaques (58.9%) had an increase in AS (change in %AS .10), 118 plaques (33.9%) had no change in %AS, and 20 plaques (5.7%) had a decrease in %AS. Two hundred and thirty plaques (66.1%) had increased in TAV (% change in TAV .20), 40 plaques (11.5%) had no change in volume, and 78 plaques (22.4%) had decreased in volume. To ensure the accuracy of change in plaque characters, we considered the change of the atherosclerotic plaque is significant if two of the three above characters (%DS, %AS, and% change in TAV ) had increased, regressed, or did not change. From the above criteria, we classified plaques as follows: 200 plaques (57.47%) had progressed, 122 plaques (35.06%) had no change, and 26 plaques (7.47%) regressed. In our results, the most statistically significant risk fac tors associated with plaque progression were DM and pre sence of dyslipidemia. As seen in Table 1, from the total of 200 progressed plaques, 64.1% (128/200) were diabetics, while none of the regressed plaques were found in patients with DM (P . 0.001). Also we found that 65% (130/200) of progressed plaques were found in patients with dyslipidemia comparable to 20% (5/26) of regressed plaques (P = 0.012). The other risk
MDCT to assess the progression of coronary atherosclerosis Table 1. Comparison between the studied groups according to risk factors. Progressed (n = 200)
Regressed (n = 26)
No change (n = 122)
No
%
No
%
No
%
DM
128
64.1
0
0.0
25
Dyslipidemia
130
65
5
20.0
Hypertension
159
79.5
16
Smoking
108
53.8
5
FH
92
46.2
5
p
χ2
MC
20.8
15.543*
,0.001*
71
58.3
8.636*
0.012*
60
107
87.5
2.139
0.288
20
66
54.2
0.363
0.866
20
56
45.8
1.274
0.593
Notes: Values were presented as numbers with percentages. χ : value of chi-square for comparing between the three studied groups. *Statistically significant at P # 0.05. Abbreviation: MC, Monte Carlo test. 2
Cases. Figures 3, 4 and 5 provide examples of progres sion and regression of coronary plaques detected by MDCT.
factors did not reach statistically significant difference between the groups. Of the 200 plaques that have progressed, 149 plaques (74.5%) were soft plaques, 36 plaques (18%) were calcific, and 15 plaques (7.5%) were mixed calcific plaques as seen in Table 2. Of the 122 stable plaques, 61 plaques (50%) were calcific plaques, 41 plaques (33.7%) were soft plaques, and 20 plaques (16.3%) were mixed calcific plaques. This proved the association between plaque stabilization and the presence of intraplaque calcium deposit and progres sion of the plaque in the absence of calcium (P = 0.001). Of the 200 plaques that progressed, 16 plaques (8%) had no remodeling, 144 plaques (72%) had positive remodel ing, and 40 plaques (20%) had negative remodeling. Of the 122 stable plaques, only 5 plaques (4.2%) had no remodeling, 66 plaques (54.1%) had negative remodeling, and 51 plaques (41.7%) had positive remodeling. Of the 26 plaques that regressed, 11 plaques (42.3%) had negative remodeling and 15 plaques (57.7%) had positive remodeling. So, there was no significant association between vascular remodeling and plaque progression (P = 0.228) (as seen in Table 3). Changes of atherosclerotic plaque over time and its association with cardiovascular risk factors. In univariate longitudinal regression models, DM and the presence of dys lipidemia and absence of calcification were significantly asso ciated with progression of any atherosclerotic plaque (Table 4 and Fig. 1). The duration of follow-up did not affect the progression or regression of the plaques significantly (Fig. 2).
Discussion
Progressive atherosclerotic disease and its clinical sequel remain the number one cause of mortality in the United States. The majority of patients with ACS present with unstable angina, acute myocardial infarction, or sudden cardiac death secondary to sudden luminal thrombosis.10 Until recently, the prevailing clinical perception of ath erosclerosis was that of advancing luminal stenosis with less attention paid to the condition of the vessel wall. In order to follow-up patients with CAD and assess the pro gression of atheromatous plaques, we need to use a noninvasive, feasibly repeatable method with low interobserver variability. MDCT enables an accurate noninvasive identification and quantification of coronary plaques. The extent of coro nary calcium is a surrogate marker for total plaque burden. However, there is a striking heterogeneity among human atherosclerotic lesions, and coronary plaques often consist of noncalcified tissue.10,11 Thus, even in coronary vessels with out calcified plaques, severe atherosclerosis may be present. Hence, a more precise assessment of coronary atheroscle rotic plaque burden and disease progression by noninva sive imaging tools that can detect and characterize calcified and noncalcified plaques can be expected to add important information, but it remains a challenge even by invasive methods.
Table 2. Comparison between the three studied groups according to plaque calcification. Progressed (n = 200)
Regressed (n = 26)
No change (n = 122)
No
%
No
%
No
%
Soft
149
74.5
0
0.0
41
33.7
Calcific
36
18
21
80.7
61
50.0
Mixed
15
7.5
5
19.3
20
16.3
p
χ2
MC
16.775*
,0.001*
Notes: χ2: value of chi-square for comparing between the three studied groups. *Statistically significant at P # 0.05. Abbreviation: MC, Monte Carlo test.
Clinical Medicine Insights: Cardiology 2015:9
49
Ayad et al Table 3. Comparison between the three studied groups according to vascular remodeling. Progressed (n = 200)
Regressed (n = 26)
No change (n = 122)
No
%
No
%
No
%
Absent
16
8
0
0.0
5
4.2
Negative
144
72
11
42.3
66
54.1
Positive
40
20
15
57.7
51
41.7
p
χ2
MC
5.457
0.228
VR
Notes: χ2: value of chi-square for comparing between the three studied groups. Abbreviations: MC, Monte Carlo test; VR, vascular remodeling.
Table 4. Binary logistic regression for factors affecting plaque progression.
Sex Age
B
S.E
Sig.
OR
95% CI
DM
LL
UL
HTN
Sex
0.231
1.288
0.858
1.260
0.101
15.729
Smoking
Age
−0.101
0.057
0.073
0.904
0.809
1.010
Dyslipid
DM
3.146
1.052
0.003*
23.246
2.956
182.785
HTN
−1.244
1.367
0.363
0.288
0.020
4.201
Smoking
−1.500
0.932
0.107
0.223
0.036
1.386
Dyslipid
2.095
1.202
0.081
8.128
0.771
85.719
FH
−1.436
1.065
0.177
0.238
0.029
1.918
ACS
−1.027
1.077
0.340
0.358
0.043
2.954
Duration
0.007
0.028
0.811
1.007
0.953
1.063
Y
−2.818
1.138
0.013*
0.060
0.006
0.556
M
−1.395
1.162
0.230
0.248
0.025
2.419
Notes: Qualitative data were described using number and percent and were compared using chi-square or Monte Carlo test. Normally quantitative data were expressed as mean ± standard deviation and compared using Student’s t-test. While abnormally distributed data were expressed using Median (Min. – Max.) and were compared using Mann–Whitney test. *Statistically significant at P # 0.05. Abbrevations: HTN, hypertension; Dyslipid, dyslipidemia; Ca, calcium.
We aimed to study the role of 64/128-MDCT using both QCA and IVUS-like parameters to assess plaque vol ume, composition, and degree of stenosis and see the changes of these parameters over time. In this study, we did follow-up of 200 patients with chest pain but without ACS for 25.9 ± 19.2 months, using a semi quantitative assessment of coronary plaque burden. We found a significantly increased TAV, %AS, and %DS in 57.47% of plaques; regression in 7.4%; and stabilization in 35.06%. Our results further indicate that there are differences in progression rate according to plaque composition as we found no significant progression for calcified plaque while noncal cified plaque progressed significantly over time (χ2 = 16.775, P , 0.0001). Progression of plaque was significantly associated with the presence of cardiovascular risk factors in adjusted analysis as DM and dyslipidemia. 50
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ACS Duration Ca-1 Y Ca-1 M 0.001
0.01
0.1
1 OR
10
100
1000
Figure 1. Predictors of plaque progression.
80 70 60
Duration (months)
Ca-1
FH
50 40 30 20 10 0 Decrease or no change
Increase
Plaque progression
Figure 2. Relation of follow-up duration and atherosclerotic plaque changes.
Previous papers have shown that MDCT is comparable to QCA angiography regarding lumen stenosis assessment9,12; but QCA is a lumenography lacking the detection of the vessel wall changes, remodeling, and plaque characterization. Similarly, IVUS and MDCT comparative studies8,10 have shown that the MDCT can reasonably evaluate atherosclerotic plaque size, remodeling, eccentricity, and composition, despite
MDCT to assess the progression of coronary atherosclerosis
Figure 3. Patient No. 9, plaque No. 19: MDCT showing regression of proximal LAD soft nonobstructive plaque: (A) baseline study and (B) follow-up study.
Figure 4. Patient No. 21, plaque No. 127: MDCT showing stable LAD mixed obstructive plaque: (A) baseline study and (B) follow-up study.
Figure 5. Patient No. 21, plaque No. 128, 129: MDCT showing progression of proximal and distal RCA soft obstructive plaques: (A) baseline study and (B) follow-up study.
the acknowledged limitations of the technique. Voros et al.13 suggested that quantitative MDCT angiography could be accept ably used in population-based approaches, given the small mean differences between MDCT and IVUS measurements. Most prior IVUS studies comparable with MDCT dem onstrated lesions in the proximal segments of the three main vessels with high accuracy, but they were not able to study the distal and branching vessels by both techniques and compar ing the plaque site and composition due to the invasive nature and long procedure of IVUS study. Butler et al.14 revealed that the extent and nature of over all CAD, defined as the cumulative stenotic and nonstenotic, calcified and noncalcified atherosclerosis burden, are underes timated by invasive coronary angiography and more accurately quantified with IVUS. MDCT is inferior to IVUS but may constitute an attractive noninvasive alternative to assess over all CAD burden.15
Plaque characterization. In our study, there was an association between plaque stabilization with the presence of calcium deposits in the plaque and plaque progression with the absence of calcium (P = 0.001). Of the 200 progressed plaques, 74.5% were soft noncalcific plaques and 50% of the stable plaques were calcific plaques. In the analysis by Lehman et al.16, 69 patients were included who presented with acute chest pain to the emergency department but initially showed no evidence of acute coro nary syndromes. All patients underwent contrast-enhanced 64-slice CT at baseline and after 2 years. There was significant progression in the mean number of cross-sections containing any plaque (16.5 ± 25.3 vs. 18.6 ± 25.5, P = 0.01) and noncalci fied plaque (3.1 ± 5.8 vs. 4.4 ± 7.0, P = 0.04) but not calcified plaque (13.3 ± 23.1 vs. 14.2 ± 22.0, P = 0.2). So, soft plaques were more liable for progression and vul nerability, and calcified plaques tend to be more stable. The study by Schmid et al.17 was conducted to measure the change in noncalcified coronary plaque volume in the left main coronary artery and in the proximal left anterior descend ing coronary artery over time using 64-slice MDCT. Fifty patients in whom noncalcified lesions had been detected on baseline MDCT received follow-up scans after an interval of 17 ± 6 months. They found that there is a significant increase of the amount of noncalcified plaque, which was observed over a mean interval of 17 months. In our study, the most statistically significant (P = 0.001) risk factor associated with plaque progression is DM and dyslipidemia. Wong et al.18 revealed that individuals with metabolic syndrome (MetS) and DM have a greater incidence and abso lute progression of coronary artery calcium (CAC) compared with individuals without these conditions, with progression also predicting coronary heart disease events in those with MetS and DM.19 This study sought to examine and compare the incidence and progression of CAC among persons with MetS and DM versus those with neither condition. The MESA (Multiethnic Study of Atherosclerosis) included 6,814 African American, Asian, Caucasian, and Hispanic adults, free of cardiovascular disease at baseline. Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals [CI]) for incident CAC were 1.7 (95% CI: 1.4–2.0), 1.9 (95% CI: 1.4–2.4), and 1.8 (95% CI: 1.4–2.2) (all P , 0.01), and absolute differences in mean progression (volume score) were 7.8 (95% CI: 4.0–11.6; P , 0.01), 11.6 (95% CI: 2.7–20.5; P , 0.05), and 22.6 (95% CI: 17.2–27.9; P , 0.01) for those with MetS with out DM, DM without MetS, and both DM and MetS, respec tively. Similar findings were seen in an analysis using Agatston calcium score. In addition, progression predicted coronary heart disease events in those with MetS without DM (adjusted hazard ratio: 4.1, 95% CI: 2.0–8.5, P , 0.01) and DM (adjusted hazard ratio: 4.9 [95% CI: 1.3–18.4], P , 0.05) among those in the highest tertile of CAC increase versus no increase. Clinical Medicine Insights: Cardiology 2015:9
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So in both studies, DM is definitely, especially if uncon trolled, associated with atherosclerotic plaque progression. In our study, dyslipidemia is the second statistically sig nificant (P = 0.012) risk factor. Of a total of 200 plaques that progressed, 130 patients (65%) were dyslipidemic patients. Hoffmann et al.19 found that the effect of statin treat ment on noncalcified plaques was significant after adjusting for LDL levels and cardiac risk factors.20,21 This study supports ours, as with dyslipidemia and uncon trolled blood levels, LDL is strongly associated with plaque progression, and controlling of blood levels of LDL with sta tins is associated with atherosclerotic plaque stabilization.
Study Limitations
The relatively small number of patients studied was the main limitation in this study. Selection bias was another limitation, as the inclusion of the patients was based on the clinicians’ opinion without clear preset recommendations. Repeating this study at a wider scale might yield different results. In addition, this being a retrospective study made us unable to take detailed history about the medications, blood pressure, and dyslipidemic and diabetic control.
Conclusion
Coronary plaque burden of patients with acute chest pain sig nificantly increases over time and the progression is dependent on plaque composition, especially for soft noncalcified plaque when compared to calcified plaque. Progression is further associated with cardiovascular risk profile at baseline. Larger studies are needed to confirm these results and to determine whether the MDCT can be used for noninvasive monitor ing and follow-up of coronary atherosclerosis in high-risk patients.
Acknowledgment
This research was originally conducted and presented for the Master of Cardiology thesis of Reem H. Laymouna, under the supervision of Mohamed A. Sobhy, Salah M. ElTahan and Sherif W. Ayad, at Alexandria University.
Author Contributions
Designed the study: SME, MAS. Analyzed the data: EMS. Wrote the first draft: SWA. Contributed to writing: RL. Arranged the paper: EMS. Made critical revisions: EMS. All authors reviewed and approved of the final manuscript. References
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